Inhibition of FKBP10 attenuates hepatic stellate cell activation and liver fibrosis via RAS signaling

Hepatic stellate cell (HSC) activation is a central driver of liver fibrogenesis. FKBP10, a collagen-associated chaperone involved in extracellular matrix remodeling, has not been fully characterized in liver fibrosis. Here, we investigated the functional role and underlying mechanism of FKBP10 in HSC activation and fibrotic progression.

FKBP10 expression and localization were examined in human cirrhotic livers of various etiologies and in multiple mouse fibrosis models. FKBP10 knockdown was performed in LX-2 cells to assess effects on HSC activation, apoptosis, and extracellular matrix (ECM) synthesis. In vivo, the therapeutic potential of FKBP10 suppression was evaluated using AAV6-GFAP-mediated delivery in both CCl₄- and BDL-induced fibrosis models. Primary HSCs were subsequently isolated from fibrotic livers for transcriptomic sequencing, and LC-MS/MS combined with co-immunoprecipitation (Co-IP) was employed to identify FKBP10-interacting proteins.

FKBP10 was markedly upregulated in human cirrhotic livers and in mouse fibrosis models. Silencing FKBP10 in LX-2 cells attenuated HSC activation, reduced ECM production, and promoted apoptosis. In vivo, AAV-GFAP-shFKBP10 efficiently targeted activated HSCs, as shown by ZsGREEN co-localization with α-SMA-positive cells, and significantly alleviated fibrosis in both CCl₄- and BDL-treated mice, accompanied by reduced activated HSC abundance, decreased collagen deposition, and improved liver histology. Transcriptomic analysis of primary HSCs revealed that FKBP10 deficiency suppresses the RAS signaling pathway, while LC-MS/MS and Co-IP identified VPS4A as a potential FKBP10-binding partner that may facilitate RAS activation.

FKBP10 promotes HSC activation and sustains their survival, at least in part through VPS4A-mediated regulation of RAS signaling. Targeting FKBP10 in HSCs provides functional, spatial, and mechanistic evidence supporting its potential as a therapeutic strategy for halting and potentially reversing liver fibrosis.